Opioid and benzodiazepine antagonists are an important component of an anesthesiologists’ armamentarium. Anesthesiologists rely on these agents for rapid reversal of adverse effects such as respiratory depression and loss of responsiveness. This may be especially important in the context of restoring ventilation in hypoxic patients either by antagonizing the ventilatory depressant effect of opioids or antagonizing the sedating properties of benzodiazepines so that patients can be prompted to breathe. Furthermore, select antagonists may also play an important role in other pathologic conditions, including tumor progression in selected types of cancer. This chapter will provide a brief overview of commonly used opioid and benzodiazepine antagonists. A summary of each reversal agent is presented in Table 7–1.

History

First synthesized in 1961, naloxone is indicated for the complete or partial reversal of opioid sedation and respiratory depression. It is also indicated for suspected opioid intoxication and has been proposed as an adjunctive agent in the management of septic shock.¹

Mechanism of Action

Naloxone is a pure opioid antagonist. Although its mechanism of action is not fully understood, in vitro studies suggest that it competes for the μ, k, and σ opiate receptor sites of the central nervous system (CNS). When administered in the absence of opioid activity, it has no effect.¹

Dosing

The most rapid onset of action is achieved by intravenous (IV) injection. Intramuscular (IM) or subcutaneous (SQ) injections are also possible but may have unreliable absorption patterns. Endotracheal administration is also an option when intravascular access is unavailable. Because the duration of action for many opioids is longer than that of naloxone, patients should be closely monitored following administration.¹

Adults

For opioid overdose, an initial IV dose of 0.4 to 2 mg may be given. This may be repeated at 2- 3-minute intervals. In the case of postoperative respiratory depression, naloxone hydrochloride can be injected in 0.04- to 0.2-mg increments at 2-minute intervals until the desired reversal is achieved. Excessive or rapid reversal can induce nausea, vomiting, sweating, or circulatory arrest.¹

Children

In suspected opioid overdose, an initial dose of 0.01 mg/kg is given. A subsequent dose of 0.1 mg/kg may be given if the initial dose does not result in adequate clinical improvement. In children with postoperative opioid respiratory depression, IV naloxone can be administered in 0.005- to 0.01-mg increments at 2- to 3-minute intervals until adequate reversal is achieved. Children should be monitored for at least 24 hours following administration.¹

Onset/Duration of Action

Onset of action for IV administration is approximately 2 minutes, and its half-life is approximately 1 hour in adults² and approximately 3 hours in neonates.^1,3,4 An adult study showed that 5 mcg/kg of IV naloxone effectively reversed respiratory depression produced by morphine for 79 minutes.⁹

Pharmacokinetics/Pharmacodynamics:

Naloxone does cross the placenta, and protein binding is relatively weak. Hepatic metabolism primarily by glucuronide conjugation produces naloxone-3-glucuronide as the major metabolite.¹

Clinical Applications

For the anesthesiologist, naloxone is most often used to partially reverse opioid-induced sedation and respiratory depression. This is done by careful titration to desired effect. Naloxone has been used in some instances to increase blood pressure for several hours in patients with septic shock; however, improved survival has not been demonstrated.¹

Adverse Effects

Given the relatively short half-life of naloxone, patients should be closely monitored beyond its duration of action to ensure adequate respiratory function and consciousness. Caution should be used when administering naloxone to newborns of mothers who have been dependent on opioids as precipitation of an acute withdrawal syndrome may occur. Patients who are physically dependent on opioids are also at risk for withdrawal syndrome. Signs of acute withdrawal may include tachycardia, diarrhea, pain, fever, rhinnorhea, sweating, nausea, vomiting, trembling, abdominal pain, and hypertension. In the neonate, convulsions, irritability, and hyperactive reflexes may be noted. Complications, including pulmonary edema, hypertension, cardiac dysrhythmias, cerebral aneurysm rupture, and cardiac arrest and sudden death, have been reported.^10,11 The antihypertensive effects of clonidine can be antagonized by naloxone, producing sudden hypertension.¹² Careful, slow titration of naloxone is recommended to prevent undesired side effects.¹²

History

First characterized in 1981,¹³ flumazenil is indicated for complete or partial reversal of the sedative effects of benzodiazepines.⁵

Mechanism of Action

Flumazenil is a competitive antagonist for the benzodiazepine recognition site on the γ-aminobutyric acid (GABA)–benzodiazepine receptor complex.⁵ It effectively reverses the effects of all benzodiazepines without altering their kinetics or bioavailability.¹⁴

Dosing

Like naloxone, flumazenil should be carefully titrated to effect to reduce the chance of adverse effects. In adults, the recommended dose is 0.2 mg IV given over 15 seconds. If desired effects are not obtained, an additional 0.2 mg/min may be given up to a total dose of 1 mg. In studies where more than 1 mg of flumazenil was given, withdrawal-like events were 2 to 5 times more likely. No more than 3 mg should be given in 1 hour. In patients who are tolerant to benzodiazepines, slower titration rates of 0.1 mg/min and decreased total flumazenil dosing may reduce the frequency of agitation and confusion. Patients who are physically dependent on benzodiazepines are at high risk for withdrawal seizures, and thus flumazanil should be used with extreme caution in this population.⁵

In children, the recommended initial dose is 0.01 mg/kg (up to 0.2 mg) IV given over 15 seconds. If desired effects are not obtained, an additional 0.01 mg/kg (up to 0.2 mg) may be given at 1-minute intervals to a maximum total dose of 0.05 mg/kg or 1 mg (whichever is lower).⁵ Flumazenil is metabolized by the liver and excreted through the kidneys.¹³

Onset/Duration of Action

Onset of benzodiazepine reversal is usually noted within 2 minutes after injection. Peak effect occurs between 6 and 10 minutes. Half-life is approximately 1 hour.^5,15 Duration of action and degree of reversal is related to dose and plasma concentrations.

Clinical Applications

Flumazenil is used to partially or completely reverse the sedating effects of benzodiazepines. In general, dose totals of 0.1 to 0.2 mg produce partial antagonism. Dose totals of 0.4 to 1 mg may produce complete reversal in patient who have received standard sedating doses of benzodiazepines.⁵ Flumazenil may also be titrated to reverse benzodiazepine overdose.